Sex-based Muscular Adaptations, Capillary Dysfunction and Functional Decline Impact Knee-related Psychosocial Outcomes After Acute Knee Injury (SMACK)

Abstract Following an Anterior Cruciate Ligament (ACL) reconstruction, females have worse outcomes; however, skeletal muscle biology and function have preferentially been studied in males. These observations suggest that there are sex-based differences in the biological mechanisms contributing to recovery of muscle function. Intriguing pilot data in this proposal show preferential impairment in the recovery of quadriceps muscle and function in women as compared to men following ACL reconstruction. This proposal seeks to test the novel hypothesis that following an ACL injury, females experience exaggerated muscle cellular deficits, hindering their recovery of strength, resulting in pronounced deficiencies in gait mechanics and disproportionally worse psychological recovery compared to males. An intriguing working hypothesis is that muscle cellular deficits precede the lower psychological recovery observed in females. By identifying the cellular and molecular foundation of sex-based differences, subsequent clinical trials can harness the power of regenerative rehabilitation approaches to improve outcomes for women after ACL injury. Three interconnected, but not dependent, aims were developed to mechanistically test the overarching hypothesis. Aim 1 will define the molecular, cellular and morphological sex-based differences in quadriceps muscle after ACL injury and reconstruction. Aim 2 will determine the effect of sex on quadriceps strength, endurance, and knee mechanics after an ACL reconstruction. Additionally, Aim 3 will determine if the biological and functional differences observed in males and females predict the psychological response in women but not men following ACL reconstruction. This proposal seeks to provide critical cellular mechanisms underlying poorer functional outcomes in females and understand the biological basis of differences between males and females.